Gj. Smits et al., CARDIOPROTECTIVE EFFECTS OF THE NOVEL ADENOSINE-A(1) ADENOSINE-A(2) RECEPTOR AGONIST AMP-579 IN A PORCINE MODEL OF MYOCARDIAL-INFARCTION, The Journal of pharmacology and experimental therapeutics, 286(2), 1998, pp. 611-618
This study examined the cardioprotective effects and pharmacology of t
he novel adenosine A(1)/A(2) receptor agonist -thienyl)-1-methyl-propy
l]amino]-3H-imidazo[4,5-b] pyridyl-3-yl] cyclopentane carboxamide) (AM
P 579), in a model of myocardial infarction. Experiments were performe
d in pentobarbital-anesthetized pigs in which myocardial infarction wa
s induced by a 40-min occlusion of the left anterior descending corona
ry artery, followed by 3 hr of reperfusion. This procedure resulted in
approximately 20% of the left ventricle being made ischemic in all te
st groups. In untreated animals, an infarct size equal to 56 +/- 5% of
the ischemic area was observed. Preconditioning, with two cycles of 5
min of ischemia followed by 10-min reperfusion, resulted in a 70% red
uction in infarct size (17 +/- 5%) relative to risk area. Administrati
on of AMP 579 30 min before ischemia (3 mu g/kg i.v. followed by 0.3 m
u g/kg/min i.v. through 1 hr of reperfusion) did not change blood pres
sure, HR or coronary blood flow but resulted in marked cardioprotectio
n: a 98% reduction in infarct size (1 +/- 1%) relative to risk area. M
oreover, whereas approximately 90% of control pigs suffered ventricula
r fibrillation during ischemia, no fibrillation was observed in animal
s treated with AMP 579. Further experiments determined the effects of
AM P 579 when administered 30 min after the onset of myocardial ischem
ia, 10 min before reperfusion. Two doses were studied: a low hemodynam
ically silent dose (3 mu g/kg + 0.3 mu g/kg/min through 1 hr of reperf
usion) and a 10-fold higher dose that did cause reductions in blood pr
essure and HR. Both doses of AMP 579 produced a comparable cardioprote
ctive effect, reducing infarct size to approximately 50% of that obser
ved in control animals. The cardioprotective effect of AMP 579 was a c
onsequence of adenosine receptor stimulation, because it was completel
y inhibited by pretreatment with the specific adenosine receptor antag
onist CGS 15943 (1 mg/kg i.v.). However, the selective A, receptor ago
nist GR 79236 (3 mu g/kg + 0.3 mu g/kg/min i.v.) did not reduce infarc
t size, which suggests that under these experimental conditions, stimu
lation of adenosine A, receptors is important for the cardioprotective
effect of AMP 579. The adenosine-regulating agent acadesine (5 mg/kg
+ 0.5 mg/kg/min i.v.) also failed to reduce infarct size. In conclusio
n, the novel adenosine A(1)/A(2) receptor agonist AMP 579 produces mar
ked cardioprotection whether administered before myocardial ischemia o
r reperfusion. Cardioprotection is not dependent on changes in afterlo
ad or myocardial oxygen demand and is a consequence of adenosine recep
tor stimulation. The pharmacological profile of AMP 579 in this model
is consistent with its potential utility in the treatment of acute myo
cardial infarction.